Inhibition and active‐site modelling of prolidase

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Abstract
Consideration of the active‐site model of prolidase led us to examine azetidine, pyrrolidine and piperidine substrate analogs as potential in vivo inhibitors of the enzyme. One of these, N‐benzyloxycarbonyl‐L‐proline, was shown to be a potent competitive inhibitor of porcine kidney prolidase (Ki= 90μM); its rapid protein‐mediated permeation of human and sheep erythrocytes suggests that it may be effective in vivo. The higher homolog, N‐benzyloxycarbonyl‐L‐pipecolic acid, was also a potent inhibitor of the enzyme while the antihypertensive drugs, captoprilR and enalaprilatR, were shown to have mild and no inhibitor effects, respectively Analysis of inhibitor action and consideration of X‐ray crystallographic data of relevant Mn2+ complexes allowed the active‐site model of prolidase to be further refined; a new model is presented in which the substrate acts as a bidentate ligand towards the active‐site manganous ion. Various aspects of the new model help to explain why Mn2+ has been ‘chosen’ by the enzyme in preference to other biologically avialable metal ions.

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